The REIC/Dkk-3 gene is known to be associated with cell immortalization, and suppression of expression of such genes in cancer cells has been reported (International Publication WO01/038523 pamphlet, Tsuji, T. et al., Biochem Biophys Res Commun 268, 20-4 (2000), Tsuji, T. et al., Biochem Biophys Res Commun 289, 257-63 (2001), Nozaki, I. et al., Int J Oncol 19, 117-21 (2001) and Kurose, K. et al., J Urol 171, 1314-8 (2004)).
The REIC/Dkk-3 gene is a member of the Dkk family, and it is suggested that such gene inhibits Wnt signal transduction via a Wnt receptor (Bafico, A. et al., Nat Cell Biol 3, 683-6 (2001) and Hoang, B. H. et al., Cancer Res 64, 2734-9 (2004)). It is reported that the Wnt gene plays multiple roles in important biological conditions, such as cell growth, differentiation, and canceration (Moon, R. T. et al., Science 296, 1644-6 (2002)).
It has been reported concerning REIC/Dkk-3 that when the full-length REIC/Dkk-3 protein is added at a concentration of 10 μg/ml to a culture solution in which peripheral blood mononuclear cells (monocytes) are cultured, the cells differentiate into dendritic-cell-like cells (International Publication WO09/119874 pamphlet).
In general, there are only a small number of references that disclose substances recognized as having the ability to induce dendritic cell(-like) differentiation from blood precursor cells. Most such substances are well-known cytokines. For instance, there are many reports on the combined use of GM-CSF and IL-4; that is, the induction of dendritic cell differentiation from monocytes through the addition of GM-CSF and IL-4 to the culture solution. This combination is called the “gold standard” for dendritic cell differentiation. In addition, as substances capable of inducing dendritic cell differentiation when used alone or in combination, TNF-alpha, IL-2, IL-3, IL-6, IL-7, IL-12, IL-13, IL-15, HGF (hepatocyte growth factor), a CD40 ligand, M-CSF, an Fit3 ligand, and TGF-β have been reported. Among these proteins, known examples of a substance capable of inducing precursor cells to differentiate into dendritic cell(-like) cells when used alone include IL-2, IL-15, HGF, and a CD40 ligand, as in the case of the full-length REIC/Dkk-3 protein. Of these, only IL-2 has been confirmed to have in vivo anticancer effects. A possible reason why GM-CSF is unable to exhibit such effects is that it induces not only anticancer immunity, but also the differentiation of immunosuppressive cells represented by bone marrow-derived immunosuppressive cells (myeloid-derived suppressor cells (MDSC)) or immunoregulatory T cells (Treg) so as to activate a “negative immune system” (Parmiani, G et al., Annals of Oncology 18, 226-32 (2007)).